JPS6143113A - Medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for treating and/or preventing disorders associated with smooth muscle contraction.

[Conventional technology]

European Patent Publication No. 76075.91748°935
35.9531B, l07423, 120426°12
0427.126311, 126350, 1263fi
No. 7 and No. 138134 describe a group of chromanols, chromenes and chromans that have antihypertensive activity.

[Problem that the invention seeks to solve]

It has been found that compounds of this type have a mechanism of action which indicates that they have potential use in the treatment of disorders associated with contractions of the smooth muscles of the gastrointestinal tract and/or the respiratory system and/or the uterus. These disorders include peptic ulcer disease, irritable bowel syndrome and diverticular disease: reversible airway obstruction and asthma; and premature birth.

[Means for solving problems]

Accordingly, the present invention provides a method for the treatment and/or prevention of disorders of the gastrointestinal tract and/or respiratory system and/or uterus in a mammal, such as a human, which method is applicable to a mammal in need of such treatment and/or prevention. Effective and/or prophylactic dose formula (
1) [In the formula, one of R and RS is hydrogen, and the other is C1-6 alkylcarbonyl% C1-6 alkoxy carbonyl% C1-6 alkylcarbonyloxy, Cj ~
, alkylhydroxymethyl, nitro, cyano, chlorine,
trifluoromethyl, CI~6 alkylsulfinyl,
C1--Akylsulfonyl.

C1-6 alkoxysulfinyl & C, ~6 alkoxysulfonyl% C, ~6 alkylcarbonylamino.

01-6arykoxycarbonylamino, IC, ~6alkylthiocarbonyl, 01-6alkoxythiocarbonyl, 01-6alkylthiocarbonyloxys
C1-6 alkyl-thiol methyl A-, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, in which the amine moiety may be substituted by 1 or 2 01-6 alkyl groups, or Cbi1 C1-6 alkylsulfonylamino C, -6 alkoxysulfinylamino or 01-6 alkoxysulfonylamino or 1d
Cz~6 alkylcarbonyl, nitro or cyano-terminated ethylenyl or 1d-C(Cz
~6 alkyl) NOH or -C(Ct~6 alkyl)
selected from the group of NNf(, or one of R1 and Rt is nido r:11cyano or 01-3 alkylcarbonyl and is methoxy or by 1-2 01-6 alkyl or C3- one of R3 and R4 is hydrogen or C1-4 alkyl, and the other is C1-4 alkyl, or R3 and R4 are
taken together are C8-5 polymethylene: rc, u hydrogen, hydroxy & C4-6 alkoxy or haC
3~, R-syloxy and Rs Fi hydrogen, or R6 and R8 together are a bond: R2 is hydrogen or C1~--, which may be substituted by hydroxy and 1 group; Is it alkyl or C, ~6-alkoxy% C, ~6 alkoxycarbonyl or hacarboxy, or C1--alkyl substituted by halogen, or C-6 alkenyl; C1
~6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano.

C1~1 carboxylic acid aryl or heteroaryl, both of which may be substituted with one or more groups or atoms selected from the group of 01~
6 alkyl group! ! 7fll is optionally substituted amino or aminocarbonyl; R1 is hydrogen or C1
~-alkyl: or R1 and R, are bonded together to form C3-4 polymethylene or -cHt-(c[(t
)n −Z −(Cut )m −(m and nli
an integer between θ and 2, m + n is l or 2, and Z is oxygen, sulfur, or NR, * (wherein R9 is hydrogen).

CI~9 alkyl, C! ~7 alkanoyl, phenyl C
1-4 alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl with 1-2 C1-6 alkyl in the phenyl or naphthyl ring, CI-6
(may be substituted with alkoxy or halogen)
or form a monocyclic or bicyclic heteroarylcarbonyl; X is oxygen or sulfur; and R
＠NCXR, the moiety is trans to the R, group when US is hydroxy, C]~6 alkoxy or C1-7 acyloxy], or a ↓ hypothetically acceptable salt or solvate thereof. It becomes more.

When one of R and R2 is hydrogen, the other is preferably selected from halogen, C1-6 alkylcarbonyl, C1-6 alkoxycarponyl, nitro or cyano. In particular, when one of R1 and R2 is hydrogen, others prefer acetyl, chlorine, nitro or cyano, especially nitro, cyano or chlorine.

When one of R1 and R3 is hydrogen, B! is preferably hydrogen.

R] and US are nitro, cyano or C3-1
When alkylcarbonyl, otherwise preferably 1 to 2 C
Amino optionally substituted by I-6 alkyl or by C8-7 alkanoyl. Especially R1 and R2
When one of them is nitro, cyano or C1-3 alkylcarbonyl, the other is amino, methylamino, dimethylamino or cetylγmino.

Most preferably one of R1 and R3 is nitro or cyano, especially cyano and the other is amino.

R1 and R1 - nitro, cyano or C1-3. .

When R is alkylcarbonyl, R is nitro, cyano or ti
The alkyl group of R1 or R2 or the alkyl moiety of the alkyl-containing group is preferably methyl or ethyl.

Preferably R3 and R4 are both C3-4 alkyl, especially both methyl.

When R6 is C1-6 alkoxy and R6 is hydrogen, preferred examples of R3 include methoxy and ethoxy, with methoxy being more preferred. R.

When is C1-7 acyloxy and R6 is hydrogen, a preferred group for R1 is unsubstituted carboxylic acyloxy such as unsubstituted aliphatic acyloxy or benzoyloxy. However, it is preferred that Rs and R6 taken together are a bond, or that R6 and R6 are both hydrogen, or especially that R6 is hydroxy and R6 is hydrogen.

R? and when R8 is not bonded together, suitable groups for R8 include hydrogen, methyl, ethyl% n- and iso-propyl, n-1 sec- and tertiary-butyl. Preferably R
8 is hydrogen or methyl, more preferably hydrogen.

Next, suitable groups for R7 are hydrogen, methyl, and ethyl.

n- and iso-propyl, n-1 secondary- and tertiary-butyl, or methyl or ethyl substituted by carboxy or chlorine, or vinyl, flob-l-
enyl, floor”-2-enyl.

1-/'? Rubinyl, p)-1-enyl, b)-2-enyl, but-3+enyl, nimethylenepropyl, 1-
Methylblo'-1-enyl, 1-/tylflobou-2-
enyl (in their E and 2 forms when stereoisomerism is present) and methyl or ethyl terminally substituted by hydroxy or methoxy. Preferably R? is methyl, ethyl, n- or iso-propyl or vinyl, especially methyl, hydroxymethyl and methoxymethyl. Preferably R2 is methyl.

Examples of R7 aryl include phenyl and naphthyl, of which phenyl is preferred.

A subgroup of R7 heteroaryls are 5- or 116-membered monocyclic or 9- or 10-membered bicyclic heteroaryls, of which 5- or 116-membered monocyclic or 9- or 10-membered bicyclic heteroaryls
Or a 6-membered monocyclic heteroaryl is preferred. Further 5-
or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains 1, 2 or 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur and more than 1 In the case of heteroatoms, they are the same or different.

Examples of 5- or 6-membered monocyclic heteroaryls containing 1, 2 or 3 Hegel atoms selected from the group of oxygen, nitrogen and sulfur are furanyl, thiophenyl, pyryl, oxazolyl,
Includes thiazolyl, imidazolyl and chiryozolyl, and pyridinyl, pyrimidyl, pyrimidyl, pyrazinyl and toriazinyl.

Preferred examples of these groups include furanyl, thiophenyl, pyryl and pyridyl, especially 2- and 3-furanyl,
2- and 3-pyryl, 2- and 3-thiophenyl and 2
−． Includes 3- and 4-pyridinyl.

Examples of 9- or 10-membered bicyclic heteroaryls containing 1, 2 or 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur are benzofuranyl, benzothiophenyl, indolyl and imidazolyl, quinolinyl and inquinolinyl and Contains kinazoninirwo. Preferred orientation of these groups 2-
and 3-benzofuranyl, 2- and 3-benzothiophenyl and 2- and 3-indolyl, and 2- and 3-quinolinyl.

Preferably, the number of optically substituted groups or atoms of the aryl or heteroaryl is 1.2.3 or 4.

Preferred examples of optically substituted radicals of aryl or heteroaryl include methyl, methoxy, hydroxy, chlorine, nitro or cyano.

When R and R are bonded together, they are preferably C4 or CS polymethylene or -CHz-(cHz)
n'-Z-(CHI)m'- (in the formula, nl is 0 or l and ml is 0 or l).

X is preferably oxygen.

Within formula (1) there is a preferred group of compounds of formula (II) where p is l or 2 and the remaining substituents are as defined in formula (1).

Examples of pharmaceutically acceptable salts of compounds of formula (1) include acid addition salts of compounds of formula CD, in which one or the other of R1 and R2 is an amino or amino-containing group, e.g. and a hydrobromic acid group.

Examples of pharmaceutically acceptable solvates of compounds of formula (1') include hydrates.

Preferably the compound of formula (1) is in substantially pure form.

Examples of compounds of formula (1) include those described in the European patent publications mentioned above.

R6 is hydrogen, hydroxy & C, ~6 alkoxy or 0
1-7 acyloxy and R6 is hydrogen (
The compound of 1) is asymmetric and therefore can exist in the form of optical isomers. The present invention includes all these isomers individually and as mixtures, eg racemates.

The compound of formula (1) is described in the aforementioned European publications, U.S. Pat. No. 4,446,113, U.S. Pat.
, 496,565 and Bo 4,510,152 and allowed U.S. patent applications 482,628 and 5921.
No. 17 (all of which are incorporated by reference) or by methods similar thereto.

Administration of a compound of formula (1) or a pharmaceutically acceptable salt thereof may be by oral or parenteral administration or (for asthma) by spray, aerosol or other conventional methods for inhalation.

Amounts effective to treat the aforementioned disorders will depend on conventional factors, such as the nature and extent of the disorder being treated and the body weight of the mammal. However, a unit dose will usually contain from 0.1 to 50, such as from 0.5 to 10, of a compound of formula (1) or a pharmaceutically acceptable salt thereof.

Unit doses are usually administered one or more times, e.g. 2.3 or 4 times a day, more usually 1 to 3 times a day, so that the total daily dose is usually 0.1 to 50 doses for an adult of 70 years old. , ■ For example, 0.5 to 10Iv (7) range, i.e. about 0.001 to 1a
g/kgZ day more commonly 0.005-0.29/kp
No toxicological effects were observed within the above-mentioned dosing range.

It is highly preferred that the compound of formula (+) or a virtually acceptable salt thereof is administered in the form of a unit dosage composition, such as a unit dosage oral or parenteral composition.

Such compositions may be prepared by mixing and suitably made for oral or parenteral administration and may themselves be tablets, capsules, oral solutions, powders, granules, troches, reconstituted powders, solutions for injections and infusions or It may be in the form of a suspension or suppository. Orally administrable compositions are particularly preferred, especially shaped oral compositions, as they are more convenient for common usage.

Tablets and capsules for oral administration are usually presented in unit doses and contain conventional auxiliaries such as binders, excipients, diluents, tabletting agents, lubricants, disintegrants, colorants, flavors, and impregnating agents. Kanakura Mu. The tablets may be coated by methods well known to those skilled in the art.

Excipients suitable for use are cellulose and mannitol.

Contains lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.

Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable impregnating agents include IJ umlauryl sulfate.

These solid oral compositions may be manufactured by conventional methods of mixing, filling or tabletting.

Repeated mixing operations may be used to distribute the active agent throughout these compositions employing large quantities of excipients.

These operations are conventionally performed by those skilled in the art.

Oral solutions include, for example, aqueous or oily suspensions and solutions.

It may be provided in the form of an emulsion, syrup or elixir or as a dry product for reconstitution with water or other suitable medium before use. These solutions can be prepared with conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents such as lecithin, monooleic acid, rubitan or non-aqueous medium (which may contain edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate; or sorbic acid and, if desired, conventional flavoring or coloring agents.

Oral formulations also include conventional sustained release formulations such as tablets or granules with enteric coatings.

For parenteral administration, liquid unit dosage forms are prepared containing a compound of the invention and a sterile vehicle. Depending on the vehicle and concentration, the compound may be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle, filtering sterilization, filling a suitable vial or ampoule, and sealing. Advantageously, auxiliary agents such as local anesthetics, preservatives and buffers are also dissolved in the vehicle. To increase stability, the composition is frozen after injection into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in a vehicle instead of being dissolved and sterilized by exposure to ethylene oxide prior to suspension in the vehicle. Advantageously, a surfactant or humectant is included in the composition to aid in uniform distribution of the compounds of the invention.

As is customary, the composition will normally be accompanied by a printed package insert when used for the relevant treatment.

The invention also provides a formula for the manufacture of a medicament for the treatment and/or prophylaxis of disorders of the gastrointestinal tract and/or respiratory system and/or uterus.
Uses of the compound of 1) or a pharmaceutically acceptable salt thereof are provided. Such treatment and/or prevention may be carried out as described above and as follows.

The present invention also provides a compound of formula (1) or a pharmaceutically acceptable carrier thereof for the treatment and/or prevention of disorders of the gastrointestinal tract and/or respiratory system and/or uterus. Provides pharmaceutical MA soles.

Such compositions may be manufactured in the manner described herein.

〔effect〕

AE pharmacological data demonstrate the activity of the compound of formula (1) in tests indicating the potential use of the compound in the treatment of disorders of the gastrointestinal tract, respiratory system and uterus.

Compound 11 is 6-cyano-3,4-dihydro-2,2-
dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-28-penz[b]hyran-3-ol and compound 2 is 6-chloro-3,4-dihydro-2,
2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]bilan-3-ol (compounds of Examples 1 and 12, respectively, of U.S. Pat. No. 4,446,113) OI). Compound 3 is trans-4-
(N-acetyl)-methylamino-6-cyano-3.4
-dihydro-2,2-dimethyl-2H-benzo[b]bilan-3-ol and compound 4 is trans-4
-(N-acetyl)-ethylamino-6-cyano-3,
4-dihydro-2,2-dimethyl-2H-benzo[bl
Pyran-3-ol (U.S. Pat. No. 4,481,2
No. 14 (compounds of Examples 5 and 1, respectively).

Biological data method (1) Portal male Sprague Dawlei isolated from rats.
wl-ey') rats (250-350!9) were sacrificed by cervical dislocation. Portal vein (length 2-3 (1) below r jμ
Krebs-Henseleit (mM)
-Hen-5eleit)/S solution under a tension of 0.8-1 g in a 10- organ bath (37 °C) containing rv
. NaCl 11s.

NaT(ω125 * Gua' ” -” 5 +
41.18 r KCI4.89 in sweet 2, Mg5
Oa 0.59, CaCe5” fbo 1.87
o 95 chir for HJ weave! A mixture of R and 5% carbon dioxide was bubbled through. Isotonic tension is determined by
es) S) Using L/in gauge and recorder 6
I recorded it e-recorded. Each preparation was allowed to equilibrate for one hour after the addition of the test compound. Added calcium (3
The ability of the compounds to inhibit contractions induced by 0.05 mM Ca (Jtt-) was determined (to reduce spontaneous contractions) on tissue soaked in Krebs-Henseleit solution containing 0.05 mM Ca (Jtt-). The contraction and inhibition of the degree of contraction by added calcium (average ±8.6-m, 6-9 tissues) were determined after a 15 minute contact time with the test compound.

C) Mesenteric arteries isolated from rabbits Mesenteric arteries (3nvn rings) were removed from male New Sealant White rabbits and given the following composition (mM):
The organ was placed in a 10 m organ bath containing Ringer's solution at a standing tension of 1.5-2.09.

NaCl1120.8: KCe5.9: Ca
Cg* Z5: Mg Cl m 1.2; HEP
A mixture of 95% oxygen and 5% carbon dioxide was bubbled through the ES 5.8 nitrogen course 11.5° bath solution. Each preparation was allowed to equilibrate for 1-1-1 hour before addition of 30mM or 90mM KCI to contract the tissue.

The ability of a test compound to relax contractions held by K (JK) is determined by evaluating the magnitude of the decrease (s, e, m, on average: 4 to 9 tissues) produced by varying the concentration of the test compound. I was asked.

Results Spontaneous Ca2+ (3mM) Compound 1 1.2 1.5 (0, fS7-7.8) (0,87-3.5) IC
, is the concentration of compound that reduces contraction by 50%. Brackets indicate 95 confidence limits.

Compound 1 thus has equal potency as an inhibitor of spontaneous contractions and their inhibition by added calcium in this isolated vascular preparation.

I.C. X lo-'M 30mMK (J 90mMK (J compound 1 5.1) 10-5M (1,5~
18) IC,. is the concentration of compound that halves the contraction caused by KCe. Brackets indicate 95chi confidence limits.

Compound I therefore antagonizes the contraction due to partial, but not total, depolarizing concentrations of potassium.

Compound l against contraction mediated by low concentrations of KO2
The effect of is consistent with compounds that hyperpolarize the membrane potential, thereby preventing the potential operating calcium channels from opening in response to depolarizing stimuli. This mechanism reduces the inward flow of calcium.

The effectiveness of compound l against high concentrations of K(J) shows that the significant depolarization by K(J overcomes the hyperpolarizing effect of compound l.

The example compounds described in the aforementioned European publications, European patent applications and US patents were also tested and found to be active in Tests I and 2.

Pharmacological Data 1. Colon Isolated from Gastrointestinal Tract Male Wista type rats (Charles River, UK) were killed by a blow to the head and a 2 cm segment of the proximal colon was excised. After gently washing all lumen contents, lower the tissue with #1fiX.

6 NaCg 118.1 mM + lG42PO4 suspended longitudinally in a l□d organ bath containing Krebs' solution.
1,18mM + NaHCOt 25mM, KC/4
．． f19mM, MfSO41, f14mM, Ca(Jt
2.52mM glucose, 11.1mM win this solution 37
℃ and 95% Ox: 5 ToCOz
This caused him to stutter constantly. Isotonic contractions were applied from the tissue with an initial tension of 1 g.

The inhibitory effect of compound 1+2 was evaluated from the decrease in the degree of spontaneous contraction of the colon. 10 accumulation vs. response curves
made up by applying the compound to the bath at intervals of minutes. I
D, (concentration of drug that reduces contraction by 50 degrees) was determined graphically from the dose-response curve.

Colon isolated from rat: Compound 1 vs. spontaneous contraction 0.12 Compound 21.7 2, Inspiratory tract (a) Guinea pig lung strip screen isolated distal guinea pig airway smooth muscle This model is based on Lurich et al. [Cd1n, Exp.

Pharm, Phys,) 6. f325~f129
(3979)) based on the method of <.

Two parenchymal lung strips were prepared 1a from each caudate lobe by cutting a strip approximately 3 mm wide from the outer edge of the confection. Standard t - 10d filled with Krebs solution at 37℃
The organ was placed in an organ bath and insufflated with 5 parts of O1. Changes in isodominant muscle tension were monitored and a static tension of 2 g was applied to the tissue (which was allowed to equilibrate for 60 minutes). During the equilibration period, the tissue Q was washed at 15 minute intervals and readjusted to a standing tension of t2g if necessary.

A submaximal dose of histamine (2X10
Van Rossum C Arc India Pharmacodein Chill (Arch.

Int, Pharmacodyn, Ther, )14
3, 299-(1983)), histamine was administered cumulatively (10-'m-10-'m
). After washing and re-equilibration, the tissue was exposed to test compound (10-' m ) for 20 minutes and then a second cumulative concentration versus contractile response to histamine was performed. Appropriate dose-response curves for histamine in the absence and presence of the test compound were drawn and the threshold and IF effects of the test compound on histamine of EDSo were recorded. The effect on maximal histamine response was also determined.

Inhibition of histamine-induced contractions is due to an increase in the threshold concentration;
ED, as indicated by an increase in value or a decrease in the maximal response induced by histamine.

伽) In-vivo guinea pig asphyxia model This model is a Herxheimer model.
') [Br, J, Pharm
) 50.

314 (1974)).

Conscious female guinea pig (Dunkin) - 1 tray (Dunkin - Hartey) m, body Ti50
0 to 700&] with a volume of approximately 8 g perspex (
per8pe! ) and the animals were exposed to a histamine aerosol. A standard histamine aerosol is prepared from a 5810-mm solution of histamic acid phosphate in distilled water.
! After obtaining satisfactory aerosol generation using an ultrasonic atomizer (power scale 7),
Time k fl from introduction of the aerosol at t when the guinea pig passes through the chamber for 0 seconds and collapses (called asphyxia collapse)
I recorded it e-recorded. The animal was quickly removed and allowed to emit sound to recover. In this way, the average time of asphyxia collapse for a group of guinea pigs was determined.

The compound was orally administered to all groups of animals, and the degree of retention in response to histamine-induced asphyxia collapse was determined by the increase in the average time; the average time of asphyxia collapse in the compound-treated group was about 80 to 100 seconds compared to the asphyxia collapse in the control group. Met. Compound-treated animals that did not collapse were considered 100% protected.

The compound is 5■/? (, 1 me/kg body weight) and the animals were nebulized with standard monohistamine aerosol 30 minutes later.

Significant differences in all increases in mean asphyxia collapse time of compound-treated groups of animals relative to those of the vehicle-treated control group were determined using the Student rtJ test.

The results are as follows.

(1) Lung strips isolated from guinea pigs.

Antagonism of histamine contraction.

Each compound was tested at 10-'M.

fil 8.5X10-7
2.2X10-1t±1.5 X 10-7
±1.4X10-'Control lX10-'
1.9X10-'±0.4X10-7
±0.3 X l O-'6
3 1XIO-'
7.8X10-6±3.3 X 10-' Control 1.7X10-' 3X10-
”±1.2X10-7 ±0.7X1
0-' None of the compounds affected the maximal response to histamine.

[b] Conscious guinea pig Histamine collapse (aerosol drop).

Test compound 30 minute pre-treatment 1 5η/yu 6 154±26”4 5
WIg/klF 4 176±25cm control 6 90±104k p<o,
os; tatami p(:o, o l.

3. Uterine potassium depolarized rats Female Svrag-Daurei rats (120-160
#')'ir killed and the uterine horns removed. Each horn was cut longitudinally to obtain muscle tissue (1) which was further divided to obtain two preparations (i.e. 4 from each animal). Ta. Each organization t-
The organ was placed in a 10 organ bath containing normal Krebs buffer at 32°C and vented with 95°C and 5°C. Approximately 4
The tissue was repeatedly stretched and washed during a 5 minute equilibration period to maintain a resting tension of 0.29. An increase in tension was induced by replacing Krebs buffer with another (sodium ions were replaced by an equal amount of potassium ions).

This caused the tissue to contract and then slow to equilibrate at a higher level than the initial resting level.

A cumulative concentration effect curve for Compound 1 was then run until the response to the final bath concentration (10-'M) stabilized. The concentration of isoprenaline was increased until the tissue was sufficiently relaxed. The results are shown as a function of this maximum slack.

Result Compound 1 Max.
18±33XlO-IM
31±3IXIO-'M 81±67 specimens were used.

Claims (9)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, one of R_1 and R_2 is hydrogen, and the others are C_1-_6 alkylcarbonyl, C_1-_6 alkoxycarbonyl, C_1- _6 alkylcarbonyloxy, C_1-_6 alkylhydroxymethyl, nitro,
Cyano, chlorine, trifluoromethyl, C_1-_6 alkylsulfinyl, C_1-_6 alkylsulfonyl,
C_1-_6 alkoxysulfinyl, C_1-_6 alkoxysulfonyl, C_1-_6 alkylcarbonylamino, C_1-_6 alkoxycarbonylamino, C
_1-_6 alkyl-thiocarbonyl, C_1-_6 alkoxy-thiocarbonyl, C_1-_6 alkyl-thiocarbonyloxy, C_1-_6 alkyl-thiol methyl, formyl or C_1-_6 alkyl with 1 or 2 amino moieties is aminosulfinyl, aminosulfonyl or aminocarbonyl optionally substituted with a group, or C_1-_6 alkylsulfinylamino, C_1-_6 alkylsulfonylamino, C_
1-_6 alkoxysulfinylamino or C_1-_
6 alkoxysulfonylamino or C_1~_
is ethylenyl terminally substituted with 6 alkylcarbonyl, nitro or cyano, or -C(C_1-_6 alkyl)NOH or -C(C_1-_6 alkyl)NN
H_2, or one of R_1 and R_2 is nitro, cyano or C_1-_3 alkylcarbonyl and the other is methoxy or 1-2 C
is amino optionally substituted by_1-_6 alkyl or by C_2-_7 alkanoyl; one of R_3 and R_4 is hydrogen or C_1-_4 alkyl and the other is C_1-_4 alkyl or R_3 and R_4 are together C_2-_5 polymethylene; R_5 is hydrogen, hydroxy, C_1_-_6 alkoxy or C_1_-_7 acyloxy and R_6 is hydrogen or R_5 and R_6 together are a bond; R_7 is hydrogen, or C_1_-_6 alkyl optionally substituted by hydroxy, or C_1_-_6 alkoxy, C_1_-_6 alkoxycarbonyl or carboxy, or C_1_-_6 alkyl substituted by halogen. or C_2_-_6 alkenyl; or C_1_-_
Aryl or heteroaryl optionally substituted with one or more groups or atoms selected from the group consisting of 6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C_1-_1_2 carboxylic acid acyl, or 1- is amino or aminocarbonyl optionally substituted by two C_1_-_6 alkyl groups; R_8 is hydrogen or C_1_-_6 alkyl; or R_7 and R_8 are bonded together to form C_3-_4 polymethylene or -CH_2 -(CH_2)n-Z-(CH_
2) m-{in the formula, m and n are integers from 0 to 2, and m+n
is 1 or 2 and Z is oxygen, sulfur or NR_9(
In the formula, R_9 is hydrogen, C_1-_9 alkyl, C_2_-
_7 Alkanoyl, phenyl C_1-_4 Alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl, with 1 to 1 in the phenyl or absent naphthyl ring
or form a monocyclic or bicyclic heteroarylcarbonyl; X is oxygen or sulfur; and the R_8NCXR_7 moiety is trans to the R_5 group when R_5 is hydroxy, C_1_-_6 alkoxy or C_1_-_7 acyloxy] or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for use in the treatment and/or prevention of disorders of the gastrointestinal tract and/or respiratory system and/or uterus. (2) One of R_1 and R_2 is hydrogen and the other is halogen, C_1_-_6 alkylcarbonyl, C_1
The composition according to claim 1, which is _ to _6 alkoxycarbonyl, nitro or cyano. (3) The composition according to claim (2), wherein R_1 is cyano or chlorine and R_2 is hydrogen. (4) The composition according to any one of claims (1) to (3), wherein R_3 and R_4 are both methyl. (5) The composition according to any one of claims (1) to (4), wherein R_5 is hydroxy and R_6 is hydrogen. (6) Claims (1) to (5) in which R_7 and R_8 are combined to form C_4 or C_5 polymethylene.
A composition according to any one of paragraphs. (7) The composition according to any one of claims (1) to (6), wherein R_7 is methyl and R_8 is methyl, ethyl or hydrogen. (8) The compound of formula (I) is represented by formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, p is 1 or 2, and the remaining substituents are The composition according to claim (1), which is a compound as defined in paragraph (1). (9) The compound of formula (I) is 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo-[b]pyran-
3-ol, 6-chloro-3,4-dihydro-2,2-
Dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol, trans-4-(N-acetyl)-methylamino-6-cyano-3,4-dihydro -2,2-dimethyl-2H-benzo[b]pyran-3-ol or trans-4-(N-
acetyl)-ethylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-
The composition according to claim (1), which is 3-ol.